Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial

被引：667

作者：

Maguire, Albert M. ^{[2
,3
]}

High, Katherine A. ^{[2
,4
,5
,6
]}

Auricchio, Alberta ^{[7
,8
]}

Wright, J. Fraser ^{[2
,15
]}

Pierce, Eric A. ^{[3
]}

Testa, Francesco ^{[9
]}

Mingozzi, Federico ^{[2
]}

Bennicelli, Jeannette L.

Ying, Gui-shuang ^{[10
]}

Rossi, Settimio ^{[9
]}

Fulton, Ann ^{[11
]}

Marshall, Kathleen A. ^{[2
]}

Banfi, Sandra ^{[7
]}

Chung, Daniel C.

Morgan, Jessica I. W.

Hauck, Bernd ^{[2
]}

Zelenaia, Olga ^{[2
]}

Zhu, Xiaosong ^{[3
]}

Raffini, Leslie ^{[4
]}

Coppieters, Frauke ^{[12
]}

De Baere, Elfride ^{[12
]}

Shindler, Kenneth S.

Volpe, Nicholas J. ^{[10
]}

Surace, Enrico M. ^{[7
]}

Acerra, Carmela ^{[9
]}

Lyubarsky, Arkady

Redmond, T. Michael ^{[13
]}

Stone, Edwin ^{[5
,6
,14
]}

Sun, Junwei ^{[2
]}

McDonnell, Jennifer Wellman ^{[2
]}

Leroy, Bart P. ^{[12
,16
,17
]}

Simonelli, Francesca ^{[9
]}

Bennett, Jean ^{[1
,2
]}

机构：

[1] Univ Penn, Stellar Chance Labs 309C, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Abramson Pediat Res Ctr, Philadelphia, PA 19104 USA

[3] Childrens Hosp Philadelphia, Dept Ophthalmol, Philadelphia, PA 19104 USA

[4] Univ Penn, Childrens Hosp Philadelphia, Dept Hematol, Dept Pediat, Philadelphia, PA 19104 USA

[5] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA

[6] Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA

[7] TIGEM, Naples, Italy

[8] Univ Naples Federico 2, Dept Pediat, Naples, Italy

[9] Univ Naples 2, Dept Ophthalmol, Naples, Italy

[10] Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA

[11] Childrens Hosp Boston, Dept Ophthalmol, Boston, MA USA

[12] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[13] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA

[14] Univ Iowa, Coll Med, Dept Ophthalmol, Carver Ctr, Iowa City, IA 52242 USA

[15] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[16] Univ Ghent, Dept Ophthalmol, B-9000 Ghent, Belgium

[17] Ghent Univ Hosp, B-9000 Ghent, Belgium

来源：

LANCET | 2009年 / 374卷 / 9701期

关键词：

VISUAL CYCLE; RETINITIS-PIGMENTOSA; VISION; MUTATIONS; BLINDNESS; ROD; ISOMEROHYDROLASE; ISOMERASE; KINETICS; SAFETY;

D O I：

10.1016/S0140-6736(09)61836-5

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5x10(10) vector genomes), medium (4.8x10(10) vector genomes), or high dose (1.5x10(11) vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.

引用

页码：1597 / 1605

页数：9

共 26 条

[1] Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness [J].

Acland, GM ;

Aguirre, GD ;

Bennett, J ;

Aleman, TS ;

Cideciyan, AV ;

Bennicelli, J ;

Dejneka, NS ;

Pearce-Kelling, SE ;

Maguire, AM ;

Palczewski, K ;

Hauswirth, WW ;

Jacobson, SG .

MOLECULAR THERAPY, 2005, 12 (06) :1072-1082

[2] Impairment of the transient pupillary light reflex in Rpe65-/- mice and humans with Leber congenital amaurosis [J].

Aleman, TS ;

Jacobson, SG ;

Chico, JD ;

Scott, ML ;

Cheung, AY ;

Windsor, EAM ;

Furushima, M ;

Redmond, TM ;

Bennett, J ;

Palczewski, K ;

Cideciyan, AV .

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2004, 45 (04) :1259-1271

[3] Effect of gene therapy on visual function in Leber's congenital amaurosis [J].

Bainbridge, James W. B. ;

Smith, Alexander J. ;

Barker, Susie S. ;

Robbie, Scott ;

Henderson, Robert ;

Balaggan, Kamaljit ;

Viswanathan, Ananth ;

Holder, Graham E. ;

Stockman, Andrew ;

Tyler, Nick ;

Petersen-Jones, Simon ;

Bhattacharya, Shomi S. ;

Thrasher, Adrian J. ;

Fitzke, Fred W. ;

Carter, Barrie J. ;

Rubin, Gary S. ;

Moore, Anthony T. ;

Ali, Robin R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (21) :2231-2239

[4]

BENNICELLI J, 2008, MOL THER, V358, P2282

[5] Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer [J].

Bennicelli, Jeannette ;

Wright, John Fraser ;

Komaromy, Andras ;

Jacobs, Jonathan B. ;

Hauck, Bernd ;

Zelenaia, Olga ;

Mingozzi, Federico ;

Hui, Daniel ;

Chung, Daniel ;

Rex, Tonia S. ;

Wei, Zhangyong ;

Qu, Guang ;

Zhou, Shangzhen ;

Zeiss, Caroline ;

Arruda, Valder R. ;

Acland, Gregory M. ;

Dell'Osso, Lou F. ;

High, Katherine A. ;

Maguire, Albert M. ;

Bennett, Jean .

MOLECULAR THERAPY, 2008, 16 (03) :458-465

[6]

BERGAMIN O, 2004, INVEST OPHTH VIS SCI, V45, P1259

[7] NATURAL COURSE OF RETINITIS PIGMENTOSA OVER A 3-YEAR INTERVAL [J].

BERSON, EL ;

SANDBERG, MA ;

ROSNER, B ;

BIRCH, DG ;

HANSON, AH .

AMERICAN JOURNAL OF OPHTHALMOLOGY, 1985, 99 (03) :240-251

[8] Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year [J].

Cideciyan, Artur V. ;

Hauswirth, William W. ;

Aleman, Tomas S. ;

Kaushal, Shalesh ;

Schwartz, Sharon B. ;

Boye, Sanford L. ;

Windsor, Elizabeth A. M. ;

Conlon, Thomas J. ;

Sumaroka, Alexander ;

Pang, Ji-jing ;

Roman, Alejandro J. ;

Byrne, Barry J. ;

Jacobson, Samuel G. .

HUMAN GENE THERAPY, 2009, 20 (09) :999-1004

[9] Vision 1 Year after Gene Therapy for Leber's Congenital Amaurosis [J].

Cideciyan, Artur V. ;

Hauswirth, William W. ;

Aleman, Tomas S. ;

Kaushal, Shalesh ;

Schwartz, Sharon B. ;

Boye, Sanford L. ;

Windsor, Elizabeth A. M. ;

Conlon, Thomas J. ;

Sumaroka, Alexander ;

Roman, Alejandro J. ;

Byrne, Barry J. ;

Jacobson, Samuel G. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (07) :725-727

[10] Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics [J].

Cideciyan, Artur V. ;

Aleman, Tomas S. ;

Boye, Sanford L. ;

Schwartz, Sharon B. ;

Kaushal, Shalesh ;

Roman, Alejandro J. ;

Pang, Ji-Jing ;

Sumaroka, Alexander ;

Windsor, Elizabeth A. M. ;

Wilson, James M. ;

Flotte, Terence R. ;

Fishman, Gerald A. ;

Heon, Elise ;

Stone, Edwin M. ;

Byrne, Barry J. ;

Jacobson, Samuel G. ;

Hauswirth, William W. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (39) :15112-15117

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